Contribution of transcription factor, SP1, to the promotion of HB-EGF expression in defense mechanism against the treatment of irinotecan in ovarian clear cell carcinoma.
Contribution of transcription factor, SP1, to the promotion of HB-EGF expression in defense mechanism against the treatment of irinotecan in ovarian clear cell carcinoma.
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DOI：
10.1002/cam4.301
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发表时间：
2014-10
期刊：
影响因子：
4
通讯作者：
Miyamoto, Shingo
中科院分区：
文献类型：
--
作者：
Miyata, Kohei;Yotsumoto, Fusanori;Nam, Sung Ouk;Odawara, Takashi;Manabe, Sadao;Ishikawa, Toyokazu;Itamochi, Hiroaki;Kigawa, Junzo;Takada, Shuji;Asahara, Hiroshi;Kuroki, Masahide;Miyamoto, Shingo
卵巢透明细胞癌是卵巢恶性肿瘤中最严重的一种组织学亚型。肝素结合表皮生长因子样生长因子（HB-EGF）是卵巢癌治疗的一个很有前途的靶点。本研究的目的是验证HB-EGF靶向治疗OCCC的疗效，并确定SN 38处理OCCC细胞诱导HB-EGF的转录因子。HB-EGF在卵巢癌细胞中呈高表达，在常规抗肿瘤药物中只有SN 38对卵巢癌细胞有抗肿瘤作用。HB-EGF的特异性抑制剂，交叉反应物质197（CRM 197），导致SN 38处理的凋亡OCCC细胞数量的协同增加。使用5′-缺失启动子构建体的荧光素酶测定鉴定了-125和-178之间的富含GC的元件（远端转录起始位点表示为+1）作为顺式调节区，并且SN 38的处理诱导了该区域的荧光素酶活性。计算机模拟和染色质免疫沉淀分析估计SP1与OCCC细胞中HB-EGF的顺式调节区结合。实时荧光定量PCR和细胞活力测定结果表明，针对SP1的小干扰RNA转染抑制了SN 38诱导的HB-EGF表达，从而增强了SN 38的敏感性。综上所述，这些结果表明，HB-EGF表达的诱导通过SP1在OCCC细胞中的转录活性而有助于抵抗SN 38处理的防御机制。
Ovarian clear cell carcinoma (OCCC) is a worst histological subtype than other ovarian malignant tumor. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a promising target for ovarian cancer therapy. The aims of this study were to validate the efficacy of HB-EGF–targeted therapy for OCCC and to identify the transcription factor that contributed to the induction of HB-EGF by SN38 treatment in OCCC cells. HB-EGF was highly expressed in OCCC cells, and an increase of HB-EGF was induced by SN38 which had only antitumor effect among conventional anticancer agents on OCCC. A specific inhibitor of HB-EGF, a cross-reacting material 197 (CRM197), led to a synergistic increase in the number of apoptotic OCCC cells with the treatment of SN38. The luciferase assay with 5′-deletion promoter constructs identified a GC-rich element between −125 and −178 (the distal transcription start site was denoted +1) as a cis-regulatory region, and the treatment of SN38 induced luciferase activity in this region. An in silico and chromatin immunoprecipitation analysis estimated that SP1 bound to the cis-regulatory region of HB-EGF in OCCC cells. Real-time PCR and cell viability assays showed that the transfection of a small interfering RNA targeting SP1 suppressed the expression of HB-EGF induced by SN38, resulting in the enhanced sensitivity of SN38. Taken together, these results indicate that induction of HB-EGF expression contributed to defense mechanism against treatment of SN38 through the transcriptional activity of SP1 in OCCC cells.
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DOI：
10.1016/j.bbrc.2007.01.047
发表时间：
2007-03-23
影响因子：
3.1
作者：
Ornskov, Dorthe;Nexo, Ebba;Sorensen, Boe S.
通讯作者：
Sorensen, Boe S.
影响因子：
11.2
作者：
Miyamoto, S;Hirata, M;Mekada, E
通讯作者：
Mekada, E
影响因子：
4.8
作者：
Gorbatenko, Andrej;Olesen, Christina W.;Pedersen, Stine F.
通讯作者：
Pedersen, Stine F.
影响因子：
45.3
作者：
Mateos, Maria-Victoria;Richardson, Paul G.;San Miguel, Jesus F.
通讯作者：
San Miguel, Jesus F.
影响因子：
4.8
作者：
Gechtman, Z;Alonso, JL;Klagsbrun, M
通讯作者：
Klagsbrun, M